Lack of association between ALOX5AP genetic polymorphisms and risk of ischemic stroke: evidence from meta-analyses

Figures & data

Figure 1 Flow diagram of study selection.

Abbreviation: CNKI, China Knowledge Resource Integrated.

Table 1 Summary of included studies

Author	Year	Sample size		Diagnostic method	Polymorphisms evaluated	Female (%)		Age		Ethnicity	NOS score
		Cases	Controls			Cases	Controls	Cases	Controls
Helgadottir et al^Citation11	2004	702	624	CT/MRI confirmed	HapA and HapB	46.9	NM	NM	20–90	Caucasians	8
Helgadottir et al^Citation12	2005	450	710	CT/MRI confirmed	HapA and HapB	42.0	49.0	66.8±0.6	67.2±0.4	Caucasians	7
Meschia et al^Citation13	2005	377	263	CT/MRI confirmed	rs17222814, rs10507391, rs4769874 and rs9551963	46.4	62.0	64.8±15.0	60.0±14.7	Caucasians	8
Lõhmussaar et al^Citation14	2005	639	736	CT/MRI confirmed	rs17222814, rs10507391, rs4769874, rs9551963 and HapA	36.9	39.3	65.0±18.2	62.0±11.7	Caucasians	7
Zee et al^Citation15	2006	259	259	CT/MRI confirmed	rs17222814, rs10507391, rs4769874, rs9551963, HapA and HapB	0.0	0.0	60.8±0.3	61.0±0.3	Caucasians	7
Zhang et al^Citation16	2006	1,285	1,713	CT/MRI confirmed	rs10507391 and rs4769874	36.7	42.7	60.4±9.2	59.6±8.5	Asians	6
Gao and Qc^Citation17	2008	100	100	CT/MRI confirmed	rs10507391 and rs4769874	35.0	40.0	57.3±6.9	60.0±7.5	Asians	7
Lövkvist et al^Citation18	2008	932	396	CT/MRI confirmed	rs17222814, rs10507391 and rs9551963	44.0	43.2	Age above 65 years: 76.2%	Age above 65 years: 78.8%	Caucasians	7
Quarta et al^Citation19	2009	294	235	CT/MRI confirmed	rs9551963 and rs4769874	40.1	43.8	68–83	60–79	Caucasians	7
He et al^Citation20	2009	412	368	CT/MRI confirmed	rs10507391	42.7	38.0	71.5±7.8	70.3±6.9	Asians	8
Cheng et al^Citation21	2010	280	258	CT/MRI confirmed	rs4073259	37.1	39.5	59.6±12.4	58.5±13.6	Asians
Domingues-Montanari et al^Citation22	2010	1,092	781	CT/MRI confirmed	rs10507391	59.3	54.0	Spain cohort: 70.6±11.9 Portugal cohort: 52.4±9.3	Spain cohort: 72.1±6.9 Portugal cohort: 63.0±6.8	Caucasians	8
Gao et al^Citation23	2010	380	425	CT/MRI confirmed	rs10507391, rs17222814, rs4769874and rs9551963	37.1	48.2	63.4±23.9	56.8±21.8	Asians	7
Kim et al^Citation24	2011	117	398	CT/MRI confirmed	rs17222919	45.3	51.3	65.5±12.1	53.8±15.2	Asians	6
Lee et al^Citation25	2011	291	278	CT/MRI confirmed	rs10507391 and rs4293222	19.9	41.0	65.4±10.6	64.1±11.1	Asians	7
Zhao et al^Citation26	2012	682	598	CT/MRI confirmed	rs17222814, rs10507391, rs4769874 and rs9551963,	40.9	43.8	62.1±9.4	61.8±10.1	Asians	7
Wang et al^Citation27	2012	658	704	CT/MRI confirmed	rs17222919	40.0	44.9	69.4±10.6	69.2±9.0	Asians	6
Sharma et al^Citation28	2013	610	610	CT/MRI confirmed	rs10507391	32.0	32.3	49.3±17.3	49.0±16.8	Asians	8
Xu et al^Citation29	2013	547	794	CT/MRI confirmed	rs9551963 and rs10507391	NM	NM	NM	NM	Asians	7
Zhang et al^Citation30	2014	501	497	CT/MRI confirmed	rs4073259	33.9	39.6	58.7±10.2	53.1±8.6	Asians	8
Yao et al^Citation31	2014	420	488	CT/MRI confirmed	rs10507391, rs4769874 and rs9551963	33.3	35.2	64.7±9.1	64.7±9.3	Asians	7
Yang et al^Citation32	2014	492	490	CT/MRI confirmed	rs10507391, rs4769874, rs9551963 and HapB	41.1	45.3	56.7±8.3	56.2±8.9	Asians	7
Fan et al^Citation33	2015	1,913	1,814	CT/MRI confirmed	rs17222919	46.6	48.4	Population 1: 56.1±10.6 Population 2: 60.5±7.8	Population 1: 55.3±10.3 Population 2: 60.5±7.8	Asians	8
Shao et al^Citation34	2015	459	462	CT/MRI confirmed	rs9551963, rs4769874, rs4769060 and rs10507391	39.9	40.3	48.6±11.0	63.8±9.2	Asians	7
Wang et al^Citation35	2015	396	300	CT/MRI confirmed	rs4769874 and rs10507391	40.9	35.3	56–71	54–75	Asians	7
Qu et al^Citation36	2015	456	452	CT/MRI confirmed	rs10507391, rs4769874, and rs9551963	34.9	33.4	59.7±11.5	53.7±8.2	Asians	7
Diakite et al^Citation37	2016	175	201	CT/MRI confirmed	rs10507391	43.4	NM	57.1±2.0	54.6±2.0	Caucasians	6
Hu et al^Citation38	2017	479	580	CT/MRI confirmed	rs10507391	11.1	12.4	65.2±5.3	65.1±5.7	Asians	7
Liu et al^Citation39	2017	346	399	CT/MRI confirmed	rs4293222	38.2	43.9	63.1±10.7	61.9±10.7	Asians	6
Shi et al^Citation40	2018	550	555	CT/MRI confirmed	rs4073259	49.8	49.9	Population 1: 60.7±12.8 Population 2: 60.5±12.5	Population 1: 60.9±13.3 Population 2: 62.5±13.2	Asians	7

Notes: HapA = SG13S25G–SG13S114T–SG13S89G–SG13S32A. HapB = SG13S377A–SG13S114A–SG13S41A–SG13S35G.

Abbreviations: CT, computed tomography; MRI, magnetic resonance imaging; NM, not mentioned; NOS, Newcastle–Ottawa Scale.

Figure 2 Forest plots for the association of ALOX5AP polymorphisms with IS risk.

Notes: (A) Meta-analysis of the ALOX5AP rs10507391 polymorphism and risk of IS using the random-effects model (A allele vs T allele). (B) Meta-analysis of the ALOX5AP rs4769874 polymorphism and risk of IS using the fixed-effects model (A allele vs G allele). (C) Meta-analysis of the ALOX5AP rs9551963 polymorphism and risk of IS using the random-effects model (A allele vs C allele). (D) Meta-analysis of the ALOX5AP rs17222814 polymorphism and risk of IS using the fixed-effects model (A allele vs G allele). Weights are from random-effects analysis.
Abbreviation: IS, ischemic stroke.

Table 2 Meta-analysis of association between ALOX5AP polymorphisms and IS risk

Polymorphism	Subgroup	Number of studies	Test of heterogeneity		Test of association		Test of publication
			I^2 (%)	P-value	OR (95% CI)	P-value	Begg’s test	Egger’s test
rs10507391	Total	20	81.6	,0.001	1.03 (0.93–1.14)	0.557	0.974	0.857
	Asians	14	81.2	,0.001	1.10 (0.98–1.23)	0.109	NA	NA
	Caucasians	6	68.7	0.008	0.89 (0.76–1.02)	0.101	NA	NA
	HWE	19	80.8	,0.001	1.05 (0.95–1.16)	0.318	NA	NA
rs4769874	Total	13	28.2	0.160	1.13 (1.00–1.28)	0.050	1.000	0.909
	Asians	9	10.9	0.344	1.10 (0.95–1.28)	0.210	NA	NA
	Caucasians	4	59.2	0.061	1.19 (0.96–1.48)	0.106	NA	NA
rs9551963	Total	12	44.7	0.047	1.03 (0.96–1.11)	0.372	0.451	0.365
	Asians	7	58.6	0.025	1.07 (0.96–1.19)	0.230	NA	NA
	Caucasians	5	0	0.484	0.98 (0.90–1.07)	0.656	NA	NA
	HWE	10	53.3	0.023	1.04 (0.95–1.14)	0.381	NA	NA
rs17222814	Total	6	25.3	0.244	1.09 (0.96–1.24)	0.195	0.256	0.137
	Asians	2	80.4	0.025	1.12 (0.89–1.41)	0.354	NA	NA
	Caucasians	4	0	0.704	1.08 (0.92–1.26)	0.348	NA	NA
rs17222919	Total	4	67.9	0.025	0.89 (0.75–1.06)	0.175	0.308	0.541
	Asians	4	67.9	0.025	0.89 (0.75–1.06)	0.175	0.308	0.541
rs4073259	Total	4	63.7	0.041	1.20 (1.00–1.45)	0.056	0.238	0.156
	Asians	4	63.7	0.041	1.20 (1.00–1.45)	0.056	0.238	0.156
HapA	Total	4	65.6	0.033	1.20 (0.91–1.56)	0.192	0.362	0.621
	Caucasians	4	65.6	0.033	1.20 (0.91–1.56)	0.192	0.362	0.621
HapB	Total	4	0	0.835	1.11 (0.90–1.38)	0.339	0.734	0.251
	Asians	1	NA	NA	1.16 (0.84–1.62)	0.370	NA	NA
	Caucasians	3	0	0.692	1.07 (0.80–1.44)	0.627	NA	NA

Abbreviations: HWE, Hardy–Weinberg equilibrium; IS, ischemic stroke; NA, not applicable.

Figure 3 Funnel plots to detect publication bias.

Notes: (A) Funnel plot analysis to detect publication bias for the ALOX5AP rs10507391 polymorphism and risk of IS. (B) Funnel plot analysis to detect publication bias for the ALOX5AP rs4769874 polymorphism and risk of IS. (C) Funnel plot analysis to detect publication bias for the ALOX5AP rs9551963 polymorphism and risk of IS. (D) Funnel plot analysis to detect publication bias for the ALOX5AP rs17222814 polymorphism and risk of IS.
Abbreviations: IS, ischemic stroke; SE, standard error.

HelgadottirAManolescuAThorleifssonGThe gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and strokeNat Genet200436323323914770184

 PubMed Web of Science ®Google Scholar

HelgadottirAGretarsdottirSSt ClairDAssociation between the gene encoding 5-lipoxygenase-activating protein and stroke replicated in a Scottish populationAm J Hum Genet200576350550915640973

 PubMed Web of Science ®Google Scholar

MeschiaJFBrottTGBrownRDPhosphodiesterase 4D and 5-lipoxygenase activating protein in ischemic strokeAnn Neurol200558335136116130105

 PubMed Web of Science ®Google Scholar

LõhmussaarEGschwendtnerAMuellerJCALOX5AP gene and the PDE4D gene in a central European population of stroke patientsStroke200536473173615731479

 PubMed Web of Science ®Google Scholar

ZeeRYChengSHegenerHHErlichHARidkerPMGenetic variants of arachidonate 5-lipoxygenase-activating protein, and risk of incident myocardial infarction and ischemic stroke: a nested case-control approachStroke20063782007201116778124

 PubMed Web of Science ®Google Scholar

ZhangWLYangXMShiJSunKHuiRTPolymorphism of SG13S114T/A in the ALOX5AP gene and the risk for stroke in a large Chinese cohortYi Chuan Xue Bao200633867868416939001

 PubMedGoogle Scholar

GaoZSQcDTo study relationship between polymorphism of SG13S114T/A and SG13S89G/A in the ALOX5AP gene and thrombotic strokeNingxia Med J2008305388390

 Google Scholar

LövkvistHSmithJGLuthmanHIschaemic stroke in hypertensive patients is associated with variations in the PDE4D genome regionEur J Hum Genet20081691117112518398440

 PubMed Web of Science ®Google Scholar

QuartaGStanzioneREvangelistaAPhosphodiesterase 4D and 5-lipoxygenase activating protein genes and risk of ischemic stroke in SardiniansEur J Hum Genet200917111448145319417766

 PubMed Web of Science ®Google Scholar

HeYLZhuMJinXPZhouYLRelationship of polymorphism of SG13S114A/T in ALOX5AP gene with atherosclerotic cerebral infarctionZhejiang Da Xue Xue Bao Yi Xue Ban200938663063320014490

 PubMedGoogle Scholar

ChengHJinQWDingXSAssociation of ALOX5AP and PDE4D genes with the risk of lacunar infarction in Nanjing city of Jiangsu provinceActa Univ Med Nanjing20103013945

 Google Scholar

Domingues-MontanariSFernández-CadenasIdel Rio-EspinolaAAssociation of a genetic variant in the ALOX5AP with higher risk of ischemic stroke: a case-control, meta-analysis and functional studyCerebrovasc Dis201029652853720357438

 PubMed Web of Science ®Google Scholar

GaoZTianGPRelationship between ALOX5AP gene single nucleotide polymorphism and stroke of Han population in Shenyang CityJ Apop Nerve Dis2010271110221026

 Google Scholar

KimDHAhnWYKimDKA Promoter polymorphism (rs17222919, -1316T/G) of ALOX5AP is associated with intracerebral hemorrhage in Korean populationProstaglandins Leukot Essent Fatty Acids2011853–411512021816595

 PubMed Web of Science ®Google Scholar

LeeJDLeeTHHuangYCALOX5AP genetic variants and risk of atherothrombotic stroke in the Taiwanese populationJ Clin Neurosci201118121634163822051033

 PubMed Web of Science ®Google Scholar

ZhaoJWangXXuJAssociation of inflammatory response gene polymorphism with atherothrombotic stroke in Northern Han ChineseActa Biochim Biophys Sin201244121023103023076369

 PubMedGoogle Scholar

WangYWangGNSunHChenCXiaoHZhangJSAssociation of ALOX5AP with ischemic stroke in eastern ChineseWorld J Emerg Med20123210811325215047

 PubMedGoogle Scholar

SharmaVDadheechSKaulSJyothyAMunshiAAssociation of ALOX5AP1 SG13S114T/A variant with ischemic stroke, stroke subtypes and aspirin resistanceJ Neurol Sci20133311–210811323746795

 PubMed Web of Science ®Google Scholar

XuCQiangLLimeiCCorrelation between cerebral infarction and ALOX5AP gene expressionCell Biochem Biophys201367389990423546934

 PubMed Web of Science ®Google Scholar

ZhangRGuoXLiXArachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene rs4073259 polymorphism not associated with ischemic stroke in the northeastern Chinese Han populationClin Neurol Neurosurg2014119646924635928

 PubMed Web of Science ®Google Scholar

YaoQZhangCZhangXSynergistic effect of ALOX5AP polymorphisms and cigarette smoking on the risk of atherosclerotic cerebral infarction in a Northern Han Chinese populationJ Clin Neurosci201421697597924411318

 PubMed Web of Science ®Google Scholar

YangDHeYLiMA novel risk haplotype of ALOX5AP gene is associated with ischemic stroke in Chinese Han populationJ Mol Neurosci201453349349924198186

 PubMed Web of Science ®Google Scholar

FanYChenHLiAA promoter polymorphism (rs17222919, -1316T/G) of ALOX5AP gene is associated with decreased risk of ischemic stroke in two independent Chinese populationsPLoS One2015103e012239325815512

 PubMed Web of Science ®Google Scholar

ShaoMYiXChiLLinJZhouQHuangRIschemic stroke risk in a southeastern Chinese population: insights from 5-lipoxygenase activating protein and phosphodiesterase 4D single-nucleotide polymorphismsJ Formos Med Assoc2015114542242924485247

 PubMed Web of Science ®Google Scholar

WangJNYangZNSuiQThe polymorphism of ALOX5AP and PDE4D gene and molecular epidemiology of the susceptibility of cerebral infarctionJ Bengbu Med Coll2015401013381340

 Google Scholar

QuZSuFZhuYA tagging ALOX5AP polymorphism and risk of ischemic stroke in a northeastern Chinese Han populationInt J Clin Exp Med2015811213432135026885075

 PubMed Web of Science ®Google Scholar

DiakiteBHamziKHmimechWNadifiSGMRAVCGenetic polymorphisms of T-1131C APOA5 and ALOX5AP SG13S114 with the susceptibility of ischaemic stroke in MoroccoJ Genet201695230330927350673

 PubMed Web of Science ®Google Scholar

HuXWangJLiYThe β-fibrinogen gene 455G/A polymorphism associated with cardioembolic stroke in atrial fibrillation with low CHA2DS2-VaSc scoreSci Rep2017711751729235504

 PubMed Web of Science ®Google Scholar

LiuDLiuLSongZHuZLiuJHouDGenetic variations of oxidative stress related genes ALOX5, ALOX5AP and MPO modulate ischemic stroke susceptibility through main effects and epistatic interactions in a chinese populationCell Physiol Biochem20174341588160229041000

 PubMedGoogle Scholar

ShiYXuLFengQAllele-specific methylation contributed by CpG-SNP is associated with regulation of ALOX5AP gene expression in ischemic strokeNeurol Sci2018391017171724

 Web of Science ®Google Scholar